1 PROJECT SUMMARY/ABSTRACT 2 This proposal is responsive to PA-17-088. The number of Americans living with Alzheimer?s disease is projected 3 to more than double from 5.6 million in 2019 to 13.8 million by 2050. This rise in Alzheimer?s disease prevalence 4 represents a serious public health concern. In 2019, Alzheimer?s disease was estimated to be the sixth leading 5 cause of death in the US and the fourth leading cause of disability adjusted life years lost. Half of the nursing 6 home population has a diagnosis of Alzheimer?s disease or another dementia. Only two available classes of 7 medications, cholinesterase inhibitors (ChEIs) and memantine have been demonstrated to slow symptomatic 8 progression of Alzheimer?s disease. Donepezil (the most widely used ChEI) has FDA indications for mild, 9 moderate, and severe Alzheimer?s disease, while memantine is indicated for moderate to severe Alzheimer?s 10 disease and has evidence supporting possible benefits in mild disease. Only ~40% of residents were treated 11 with either medication class at the time of nursing home admission historically (2006), and a small minority (10%) 12 received combination therapy. Nursing home residents may be at higher risk for adverse drug events from drug- 13 drug and drug-disease interactions due to a high burden of polypharmacy and comorbidities. Yet in the DOMINO 14 clinical trial conducted among community dwelling patients, discontinuation of a ChEI before the end stages of 15 the disease was associated with worse clinical outcomes. Nearly a quarter of nursing home residents treated 16 with ChEIs and/or memantine at the time of admission discontinued treatment shortly after admission (regardless 17 of dementia severity) and were potentially at risk for clinical worsening and the need to use more hazardous 18 drugs such as antipsychotics. Using contemporaneous, national, federally-mandated Minimum Data Set 3.0 19 linked to Medicare Part A and D claims, study aims are to: 1) examine contemporary patterns of ChEI, 20 memantine, and psychotropic medication use in NH residents with Alzheimer?s disease; 2) compare long-term 21 effectiveness, safety, and survival between residents initiating combination therapy, monotherapy, and no 22 treatment with ChEIs and memantine; and 3) identify resident characteristics (e.g., dosing, comorbid conditions, 23 concurrent medications, dementia stage) for whom treatment with ChEIs and/or memantine confers a net clinical 24 benefit. The proposed R01 is responsive to calls for well-designed long-term studies of ChEIs and memantine. 25 By expanding the evidence base to facilitate a dynamic resident-centered decision-making process regarding 26 Alzheimer?s disease treatment in an aged nursing home population, this proposal fulfills the goals of The National 27 Plan to Address Alzheimer?s Disease to effectively treat Alzheimer?s disease and to optimize care quality and 28 efficiency. This research is also closely aligned with the National Institute on Aging?s Strategic Goal to improve 29 the safe use of medications.